The primary investigative interests of this laboratory are the study of human receptors for immunoglobulin (Fcg receptors) and their polymorphisms. Different receptor isoforms and polymorphic forms have distinct functional capacities with clear contributions to host defenses and to the pathogenesis of autoimmune disease. Several critical observations underscore the important role of Fcg receptors : (1) FcgR are essential to the inflammatory response in animal models of immune complex disease; (2) Fcg dependent phagocyte function is abnormal in human immune complex disease (systemic lupus erthematosus is the classic example); (3) FcgR allelic forms are abnormally distributed in human autoimmune diseases. These observations, coupled with emerging knowledge about the diversity in receptor structure and function, focus attention on several critical questions.

Signal transduction of FcgR isoforms. Different receptor isoforms have distinct functional capacities as evidenced both by the proximal signaling elements engaged and by the cell programs elicited. Such differences provide the basis for the unique contributions of allelic forms to host defenses and to autoimmunity. Early tyrosine phosphorylation is a common theme, and studies are underway to define the different signaling pathways engaged by each receptor type and their regulation by other receptor systems. Such studies will provide important approaches to the understanding and therapeutic manipulation of the diverse biologic responses elicited by lgG ligand.

Allelic polymorphisms and receptor function. Allelic variants of Fcg receptor isoforms can strongly influence receptor function. The R131/H131 variants of FcgRIIA alter the ability of the receptor to bind human IgG2 and impact on the risk of serious infection by encapsulated bacteria and of renal disease in systemic lupus erythematosus. Allelic variants of FcgRIIIB determine risk of severe kidney damage in vasculitis. Studies are now underway to define the basis for these differences and to identify new and physiologically significant polymorphic forms affecting the function of immune effector systems.